JP2022511400A - Pharmaceutical composition containing hydroxyethyl quercetin glucuronide - Google Patents

Abstract

Hydroxyethylquercetin glycosides comprising compounds of structural formulas I, II, III and IV are disclosed herein. The disclosed compounds inhibit the metabolism of norepinephrine and treat prenatal and postnatal depression in subjects in need of treating prenatal and postnatal depression. It is useful.

Description

Hydroxyethylrutoside is a semi-synthetic molecule produced by reacting the plant chemical flavonoid rutin with ethylene oxide. See U.S. Pat. No. 3,420,815. Hydroxyethylrutoside has been used in Europe for the past 40 years under the trade names VENORUTON® and PARAVEN ™ for chronic venous insufficiency and hemorrhoids. The main components of VENORUTON® are 7-monohydroxyethylrutoside (also called monoHER), 7,4'-dihydroxyethylrutoside, 7,3', 4'-trihydroxyethylrutoside (also called troxerutin). (Called), 5,7,3', 4'-tetrahydroxyethylrutoside, and 7,3', 4'-trihydroxyethylquercetin. Kendall, Br. J. Pharmacol. , 1993, 110, 199-206 and van Acker, Br. J. Pharmacol. , 1995, 115, 1260-64.

VENORUTON® is often administered to pregnant women several times daily. Titapunt, J. et al. Med. Assoc. Thai, 2001, Oct. 84 (10) 1395-400 (twice daily for pregnant women with hemorrhoids), Wijayanegara, J. Mol. Int. Med. Res. , 1992 Feb. , 20, 1,54-60 (97 pregnant women, twice a day), Bergstein, J. Mol. Intl. Med. Res. , 1975, 3,189-93 (double-blind in a total of 69 pregnant women, after 28 weeks, 3 times a day).

Hydroxyethylrutoside metabolites are provided herein. This compound can be used to inhibit the metabolism of norepinephrine in subjects who need to inhibit the metabolism of norepinephrine. Compositions and methods comprising a metabolite of hydroxyethylrutoside are also provided herein.

One embodiment is a compound comprising a metabolite of hydroxyethylrutoside or a pharmaceutically acceptable salt thereof. Also provided is a composition (eg, a pharmaceutical composition) comprising a metabolite of hydroxyethylrutoside or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or diluent.

In another aspect, the present disclosure is a method of inhibiting the metabolism of norepinephrine in a subject in need of inhibiting the metabolism of norepinephrine, wherein the subject is administered with a compound (eg, an effective amount of the compound). Including, the compound provides a method, which is a metabolite of hydroxyethylrutoside or a pharmaceutically acceptable salt thereof. Compounds for use in inhibiting the metabolism of norepinephrine, which are metabolites of hydroxyethylrutoside or pharmaceutically acceptable salts thereof, are also provided. Also provided is the use of a metabolite of a hydroxyethylrutoside compound or a pharmaceutically acceptable salt thereof for the production of a pharmaceutical for inhibiting the metabolism of norepinephrine.

Hydroxyethylquercetin-O-glucuronide or a pharmaceutically acceptable salt thereof is also provided herein. Also provided is a composition (eg, a pharmaceutical composition) comprising hydroxyethylquercetin-O-glucuronide or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or diluent.

In one aspect, the present disclosure is a method of inhibiting the metabolism of norepinephrine in a subject requiring inhibition of the metabolism of norepinephrine, wherein the subject is hydroxyethylquercetin-O-glucuronide or pharmaceutically acceptable thereof. Provided are methods comprising administering a salt (eg, an effective amount of hydroxyethylquercetin-O-glucuronide or a pharmaceutically acceptable salt thereof). Compounds are also provided that are compounds for use in inhibiting the metabolism of norepinephrine, wherein the compound is hydroxyethylquercetin-O-glucuronide or a pharmaceutically acceptable salt thereof. Also provided is the use of a metabolite of hydroxyethylquercetin-O-glucuronide or a pharmaceutically acceptable salt thereof for the production of a pharmaceutical for inhibiting the metabolism of norepinephrine.

Another embodiment is a compound comprising hydroxyethylquercetin-7-O-glucuronide or a pharmaceutically acceptable salt thereof. Also provided is a composition (eg, a pharmaceutical composition) comprising hydroxyethylquercetin-7-O-glucuronide or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or diluent.

In another aspect, the present disclosure is a method of inhibiting the metabolism of norepinephrine in a subject in need of inhibiting the metabolism of norepinephrine, wherein the subject is administered with a compound (eg, an effective amount of the compound). Including, the compound provides a method, which is hydroxyethylquercetin-7-O-glucuronide or a pharmaceutically acceptable salt thereof. Compounds are also provided that are compounds for use in inhibiting the metabolism of norepinephrine, wherein the compound is hydroxyethylquercetin-7-O-glucuronide or a pharmaceutically acceptable salt thereof. Also provided is the use of hydroxyethylquercetin-7-O-glucuronide compounds or pharmaceutically acceptable salts thereof for the production of pharmaceuticals for inhibiting the metabolism of norepinephrine.

In another aspect, the present disclosure is a method of inhibiting the metabolism of norepinephrine in a subject requiring inhibition of the metabolism of norepinephrine, wherein the subject is a metabolite of hydroxyethylrutoside or pharmaceutically acceptable thereof. Provided are methods comprising administering an effective amount of a composition comprising a salt (eg, a pharmaceutical composition).

In one embodiment, the composition comprises hydroxyethylquercetin-7-O-glucuronide or a pharmaceutically acceptable salt thereof.

In one embodiment, the composition comprises hydroxyethylquercetin-7-O-glucuronide or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or diluent.

A composition (eg, a pharmaceutical composition) for use in inhibiting the metabolism of norepinephrine in a subject requiring inhibition of the metabolism of norepinephrine, the metabolite of hydroxyethylrutoside or pharmaceutically the same thereof. Compositions comprising acceptable salts are also provided. A composition (eg, pharmaceutical composition) for use in inhibiting the metabolism of norepinephrine in a subject requiring inhibition of the metabolism of norepinephrine, the hydroxyethylquercetin-7-O-glucuronide or a pharmaceutical thereof. Also provided is a composition comprising a pharmaceutically acceptable salt and a pharmaceutically acceptable carrier or diluent. Also provided is the use of a metabolite of hydroxyethylrutoside or a pharmaceutically acceptable salt thereof for the production of a pharmaceutical for inhibiting the metabolism of norepinephrine in a subject. Also provided is the use of hydroxyethylquercetin-7-O-glucuronide or a pharmaceutically acceptable salt thereof for the production of a pharmaceutical for inhibiting the metabolism of norepinephrine.

Another aspect is structural formula I:

の化合物又はその医薬的に許容される塩である。構造式Ｉの化合物又はその医薬的に許容される塩と、医薬的に許容される担体又は希釈剤と、を含む、組成物（例えば、医薬組成物）もまた提供される。

Or a pharmaceutically acceptable salt thereof. Also provided is a composition (eg, a pharmaceutical composition) comprising a compound of Structural Formula I or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or diluent.

In another aspect, the present disclosure is a method of inhibiting the metabolism of norepinephrine in a subject requiring inhibition of the metabolism of norepinephrine, wherein the subject is a compound of Structural Formula I or a pharmaceutically acceptable salt thereof. Provided are methods comprising administering (eg, an effective amount of a compound). Compounds for use in inhibiting the metabolism of norepinephrine, wherein the compound is represented by Structural Formula I or is a pharmaceutically acceptable salt thereof, are also provided. Also provided is the use of a compound of Structural Formula I or a pharmaceutically acceptable salt thereof for the manufacture of a pharmaceutical for inhibiting the metabolism of norepinephrine.

Another aspect is Structural Formula II :.

の化合物又はその医薬的に許容される塩である。構造式ＩＩの化合物又はその医薬的に許容される塩と、医薬的に許容される担体又は希釈剤と、を含む、組成物（例えば、医薬組成物）もまた提供される。

Or a pharmaceutically acceptable salt thereof. Also provided is a composition (eg, a pharmaceutical composition) comprising a compound of Structural Formula II or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or diluent.

In another aspect, the present disclosure is a method of inhibiting the metabolism of norepinephrine in a subject requiring inhibition of the metabolism of norepinephrine, wherein the subject is a compound of Structural Formula II or a pharmaceutically acceptable salt thereof. Provided are methods comprising administering (eg, an effective amount of a compound). Compounds for use in inhibiting the metabolism of norepinephrine, which are represented by Structural Formula II or are pharmaceutically acceptable salts thereof, are also provided. Also provided is the use of a compound of Structural Formula II or a pharmaceutically acceptable salt thereof for the manufacture of a pharmaceutical for inhibiting the metabolism of norepinephrine.

An exemplary embodiment will be described below.

The compounds described herein include those generally described and are further exemplified by the classifications, subclasses, and species disclosed herein. As used herein, the following definitions shall apply unless otherwise stated. For the purposes of the present invention, chemical elements are identified according to the Periodic Table of the Elements, CAS Edition, Handbook of Chemistry and Physics, ^75th Ed. In addition, the general principles of organic chemistry are "Organic Chemistry", Thomas Sorrell, University Science Books, ^Sausalito : 1999 and "March's Advanced Organic Chemistry", 5. , Ed. : Smith, M.M. B. and March, J.M. , John Wiley & Sons, New York: 2001, the entire contents of which are incorporated herein by reference.

Unless otherwise specified herein, the nomenclature used herein is generally Nomenclature of Organic Chemistry, Sections A, B, C, D, E, F, and H, Pergamon Press, Oxford. , 1979, which is incorporated herein by reference with respect to its chemical structure name and chemical structure nomenclature. Optionally, compound names may be generated using a chemical nomenclature program (eg, CHEMDRAW®, version 17.0.0.206, PerkinElmer Information, Inc.).

The compounds of the present invention are as described in, for example, EL Eliel and SH Wilen, Stereo-chirality of Carbon Compounds, John Wiley & Sons, New York, 1994, pages 1119-1190). It may have an asymmetric center, a chiral axis and / or a chiral plane, and may occur as a racemate, racemic mixture and / or individual diastereomers or enantiomers, including optical isomers unless otherwise stated. All possible isomers and mixtures thereof are included in the invention.

As used herein, the articles "a", "an" and "the" are to be understood to include multiple referents, unless expressly stated otherwise in the context. The terms "comprising," "having," and "including" are intended to be non-limiting and mean that additional elements other than those listed may exist.

"Ethyl" is an alkyl substituent derived from ethane (C ₂ H ₆ ).

"Hydroxy" means -OH.

As used herein, the term "pharmaceutically acceptable salt" is within the scope of sound medical practice and is human and inferior without undue toxicity, irritation, allergic reactions, etc. A salt that is suitable for use in contact with animal tissue and is commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge et al. Pharmaceutical Sciences, 1977, 66, 1-19, describe in detail pharmaceutically acceptable salts, the related teachings of which are incorporated herein by reference in their entirety. Pharmaceutically acceptable salts of the compounds described herein include suitable inorganic and organic acids suitable for the treatment of interest and salts derived from inorganic and organic bases.

Exemplary inorganic bases that form suitable salts include, but are not limited to, lithium hydroxide, sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide or barium hydroxide. Exemplary organic bases that form suitable salts include aliphatic, alicyclic or aromatic organic amines such as methylamine, trimethylamine and picoline, or ammonia. Appropriate salt selection criteria will be known to those of skill in the art.

Salts derived from suitable bases include alkali metals, alkaline earth metals, ammonium and N ⁺ ((C ₁ to C ₄ ) alkyl) ₄ salts. Typical alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium and the like. Further pharmaceutically acceptable salts are optionally formed using counterions such as halides, hydroxides, carboxyls, sulfuric acids, phosphoric acids, nitrates, lower alkyl sulfonic acids and aryl sulfonic acids. Included are non-toxic ammonium, quaternary ammonium, and amine cations.

Furthermore, unless otherwise specified, the structures shown herein also imply that they include compounds that differ only in the presence of one or more isotope-rich atoms. For example, compounds produced by replacement of hydrogen with deuterium or tritium, or carbon with ¹³ C or ¹⁴ C enriched carbon are within the scope of the invention. Such compounds are useful, for example, as analytical tools, as probes in biological assays, or as therapeutic agents according to the invention.

Administration of Hydroxyethylrutoside in Pregnant Women Bergstein, J. Mol. Intl. Med. Res. , 1975, 3,189-93 (double-blind in a total of 69 pregnant women, after 28 weeks, 3 times a day) is hydroxyethylrutoside for pregnant women with dilated tortuous veins in question. It was reported that oral administration of the drug resulted in an infant with a good Apgar score. Similarly, Posfai, Cent. Eur. J. Med. , 9, 6, 2014,802-806, from an epidemiological point of view, administration of hydroxyethylrutoside to 1,143 pregnant women resulted in a significant and slight (about 100 g) increase in birth weight. It was reported that it resulted in a significant 40% reduction in births of low birth weight. Posfai, J. et al. Maternal-Fetal Neonatal Medicine, 27,11,2014,1093-8 had a 20% overall reduction in birth defects with the use of hydroxyethylrutin in the same data set, but hydroxy in early pregnancy. We reported that there was a slight increase in some specific ear-related birth defects with the use of ethylrutin. Paper, Congenit. Anom. (Kyoto), 2011 Sept. , 51, 3, 126-37 have also reported ear-related congenital defects among pregnant women using hydroxyethylrutoside, with more than half of such cases being 2 months or 3 months gestation. Noting that it included use during the months, it was concluded that hydroxyethylrutoside was contraindicated in pregnant women at the 2nd and 3rd months. Therefore, it can be reasonably concluded that it is safe to administer hydroxyethylrutoside to pregnant women in the second and third trimesters.

Other reports of the use of hydroxyethyl rutin in pregnant women include Titapant, J. Mol. Med. Assoc. Thai, 2001, Oct. 84 (10) 1395-400 (pregnant women with hemorrhoids twice daily, 53 patients, 16-34 weeks), Son, Zentralbl. Gynacol. , 1995, 117 (4) 190-7 (17 pregnant women), Wijayanegara, J. Mol. Int. Med. Res. , 1992 Feb. , 20, 1, 54-60 (97 pregnant women, twice a day), Lefebvre, Rev Fr. Gynecol. Obstet. , 1991 Feb. 25,86 (2 Pt 2) 206-8 (12 pregnant women, 4 grams per day for 30 days), Marhic, Rev. Fr. Gynecol. Obstet. , 1991 Feb. 25,86 (2 Pt 2) 209-12 (30 pregnant women, 4 grams / day after the 4th month). None of the summaries of these reports showed onset problems in infants.

Two different hydroxyethylrutosides contained in VENORUTON® are associated with correcting cortisol-related problems. Azarfarin, Iran J. et al. Basic Med. Sci. , 2018, 21, 781-6 reported that troxerutin reduced cortisol levels in depressed stressed rats. Ruijters, Pharmacol. Res. , 2014, Jan. , 79, 28-33 reported that monoHER (7-mono-O-hydroxyethylrutoside) protects the appropriate cortisol response and reduces cortisol tolerance in vitro. These reports report that the rutin prodrugs hyperoside, isoquercetin and Michelianin significantly down-regulated the circulating plasma levels of ACTH and corticosterone by 40-70% in rats, respectively. Planta Med. , 2004, Oct. , 70 (10), 1008-11.

In a related paper, Bayandor, Archives Physiol. Biochem. , DOI: 10.1080 / 13813455.2018.1443142 report that administration of troxerutin to pregnant rats fed a high-fat diet reduced anxiety and depressive behavior in offspring.

Hydroxyethylrutosides, such as troxerutin, appear to be beneficial for depressed subjects, but in this document troxerutin is associated with high inter-individual variability, thereby in a completely different individual. It has been reported that plasma troxerutin metabolites end up at distinctly different levels because the same troxerutin dose is treated differently. When this occurs, some members of the group receive healthy doses, but a significant proportion within the group receive substantially inappropriate doses.

Inter-individual variability is typically represented by calculating the coefficient of variation (COV), which is defined as standard deviation / mean. Here, the standard deviation is the standard deviation associated with the mean. Typically, if the COV of the sample population is at least about 40%, then the sample population is considered to have high inter-individual variability.

The literature includes references reporting both the mean and standard deviation of human plasma concentrations of orally delivered hydroxyethylrutoside, such as troxerutin. These are as follows.

As shown in Table 1, the COV associated with hydroxyethylrutoside / troxerutin is about 50%, which indicates that there is a relatively large inter-individual variation associated with their oral delivery in humans. It is thought to show.

Flavone glycosides (eg, troxerutin) can be absorbed in the stomach, small intestine and colon respectively. Absorption in the stomach and small intestine is substantially direct, but in the colon there are first various levels of microbial flora involved in the reaction with glucoside flavones (eg, glucoside hydrolysis and C-ring cleavage) prior to absorption. As a result, significant inter-individual variability is introduced. For example, the literature states that "low inter-individual variability is present in (flavonoid glycoside) metabolites derived from absorption in the small intestine compared to (flavonoid glycoside) catabolites derived from the action of the microflora in the colon." reported. Almeida, Comp Reviews Food Science Food Safety, 2018. Therefore, colon-mediated absorption should be avoided if it is desired to minimize inter-individual variability of orally delivered flavone glycosides.

Glucuronide flavones are thought to be absorbed in the stomach and upper small intestine. For example, Xing, Acta Pharma. Sinica, 2011, 32,655-663 report that scuteralin (flavone glucuronide) is absorbed primarily in the stomach or upper small intestine. Xing further stated that the low pH of the stomach is advantageous for neutral species (because the pKa of scutelarin is about 2.7) and absorption. Liu, Zhong Guo Zhong Yao Za Zhi, 2006 Jun; 31 (12): 999-1001 reported that baicalin (flavone glucuronide) was preferentially absorbed in the stomach of rats. Taiming, J.M. Pharm Sci. , 2006 Jun; 95 (6): 1326-33 also reported that baicalin (flavone glucuronide) was preferentially absorbed in the stomach of rats. Juergenliemk, Planta Med. , 2003 Nov. , 69, 11, 1013-7 reported that Michelianin (quercetin-3-glucuronide) was absorbed in the small intestine. Xia, Mol. , Pharm. , 2012 Nov. 5, 9, 11, 3246-58 reported that ugonoside (flavone glucuronide) was absorbed in the upper small intestine. Neither Xia nor Juergenliemk reported gastric-based perfusion tests, so neither can rule out gastric absorption. From these reports, the small intestine / stomach wall has the enzyme required to cleave the glucuronic acid moiety from the flavone glucuronide to produce an absorbable aglycone, and the flavone glucuronide is preferentially absorbed from these sites. It is possible to determine that.

Since glucuronide flavones appear to be absorbed in the stomach and upper small intestine, glucuronide flavones can substantially avoid the colon, thereby exhibiting lower inter-individual variability than the corresponding glucoside flavones (such as troxertin). A review of the literature shows that the COV associated with oral delivery of flavone glucuronide is substantially lower than the COV associated with hydroxyethylrutoside (above shown to be about 50%). 1).

For example, as shown in Table 2, the average human plasma CMax COV associated with oral delivery of scuteralin (flavone-7-O-glucuronide) is only about 33%, the average human plasma associated with oral delivery of scuteralin. AUC COV is only about 22%.

Similarly, the COV levels in human urine associated with oral delivery of flavone glucuronide are also low. Lai, Biol. Pharm. Bull. , 26, 1, 2003, 79-93 reported that oral delivery of baicalin / ogonoside (which is a flavone-7-O-glucuronide, respectively) in humans results in very low urinary COV. Lai reports oral ingestion of doses of 616 mg of baicalin and 52.5 mg of baicalein (90% of the baicalin / baicalein dose is baicalin), and the baicalin metabolite produces about 10% urinary COV. I found that I brought it. Lai also reported oral ingestion of doses of ogonoside (117.2 mg) and wogonin (32 mg), with 80% of the ugonoside dose being ugonoside, again with about 10 ugonoside metabolites. It was found to result in% urinary COV.

This document reports that oral delivery of the phytochemical substance flavon-7-O-glucuronide in humans results in very low plasma and urinary COV, thus the 7-O-glucuronide of hydroxyethylrutoside. Oral delivery of metabolites will also likely result in low COV.

Accordingly, the present invention solves the problem of high inter-individual variability associated with hydroxyethylrutoside by providing metabolites of the parent molecule in glucuronide form.

Despite the presence of glucuronide groups, flavone-7-glucuronide is known to be less water soluble. For example, Chen, Cancer Lett. 2014 Nov 1; 354 (1): 5-11 reports that baicalin is sparingly soluble in water, while Xiao, Eur J Pharm Sci. 2016 Oct 10; 93: 456-67 reported that scutelarin is sparingly soluble in water. Therefore, it can be reasonably determined that hydroxyethylquercetin-7-O-glucuronide is also sparingly soluble in water. This lack of water solubility can affect the ability of 7-O-glucuronide to access adjacent cells containing the glucuronidase required for deconjugation required to cross the gastric / small intestinal wall. Therefore, in some embodiments, hydroxyethylquercetin glucuronide is in the form of salts such as sodium salts. In some embodiments, the salt can be made by simply mixing a stoichiometric amount of glucuronide with sodium hydroxide or sodium bicarbonate. It is believed that the salt of glucuronide is preferably water soluble, thereby improving the oral bioavailability of glucuronide.

This lack of water solubility can affect the ability of glucuronide to access adjacent cells containing the glucuronidase required for deconjugation required to cross the gastrointestinal wall. Therefore, in some embodiments, the mono-3'-hydroxyethylquercetin-glucuronide is in the form of a salt such as a sodium salt. Accordingly, in some embodiments, a pharmaceutical composition comprising a salt comprising hydroxyethylquercetin-7-O-glucronate and a pharmaceutically acceptable carrier is provided. In some embodiments, the hydroxyethyl quercetin-7-O-glucronate is monohydroxyethyl quercetin-7-O-glucronate.

As explained above, at least two researchers (Liu and Taiming) have reported that flavone glucuronide is preferentially absorbed in the stomach. Since the stomach lacks a microbial flora with high inter-individual variability, it is believed that preferential absorption in the virtually microbial-free stomach may be the reason for the low inter-individual variability of flavone glucuronide. Therefore, in some embodiments, the present disclosure provides compositions designed to increase gastric absorption of flavone glucuronide.

One way to increase gastric absorption of flavone glucuronide is to increase the residence time of molecules in the stomach. The literature reports that eating a meal increases the time to expel gastric contents. However, these diets typically raise the pH of the stomach contents to about 3-4 (ie, above the pKa of flavone glucuronide), resulting in an amount of protonated flavone glucuronide species suitable for absorption. It also has the effect of substantially reducing. Therefore, the following problems arise.
-The fasting stomach has a low pH and provides the desired protonated (neutral) glucuronide morphology, but drains water within only 15 minutes (t1 / 2) (Okabe, Brit. J. Anasthesia, 114). , 1, 77-82, 2015), thereby allowing intragastric exposure to glucuronide for only 15 minutes.
-The post-feeding stomach has a long gastric emptying time (about 3 hours), but its higher pH results in an undesired anionic glucuronide form that is poorly absorbed.

Therefore, the challenge of delivering the desired neutral glucuronide with a long gastric residence time is presented.

In an attempt to solve this problem, it was observed that a 200 mL pH 2 acidic solution (eg 0.1N citric acid) increased the gastric emptying time (t1 / 2) to 60 minutes. Leodorter, Aliment Pharmacol. The. , 1999 Aug. , 13 (8), 1057-62. This corresponds to a 4-fold increase in gastric emptying time. Therefore, in some embodiments, about 300 mL of a low pH acidic medium (eg, 0.1N citric acid (about 6 g per liter), white vinegar (pH 2.4) or lime juice (pH 2-2.5)). Is provided as a method for using the glucuronide composition of the present invention as an oral liquid medium for oral ingestion. When the combination of the composition and a low pH acidic medium is ingested on an empty stomach, it retains the glucuronide (which is likely to have about 2.7 pKa) in its protonated form while the gastric retention time of the glucuronide. Has the effect of increasing.

In other embodiments, about 450 mg of betaine HCl (pH about 1) can be used as the acidifying agent.

The low pH helps ensure that the glucuronate anion formed by salt lysis is converted to a neutral glucuronide species that is better absorbed from the stomach wall than the anionic glucuronate form formed during salt lysis. Therefore, it is believed that providing an increase in the volume of low pH gastric contents also assists in salt pharmacokinetics.

One embodiment of a compound is a compound comprising a metabolite of hydroxyethylrutoside (eg, monohydroxyethylrutoside, dihydroxyethyltoside, trihydroxyethyltoside) or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is a metabolite of troxerutin.

Another embodiment is a compound comprising a hydroxyethyl quercetin glycoside (eg, monohydroxyethyl quercetin glycoside, dihydroxyethyl quercetin glycoside, trihydroxyethyl quercetin glycoside) or a pharmaceutically acceptable salt thereof. In certain embodiments, the hydroxyethyl quercetin glycoside is a monohydroxyethyl quercetin glycoside (eg, mono-3'-O-hydroxyethyl quercetin glycoside, mono-4'-O-hydroxyethyl quercetin glycoside, mono-7-O-hydroxy. Ethylquercetin glycoside, monohydroxyethylquercetin glucuronide). Mono-4'-hydroxyethylquercetin glucuronide is available from BOC Sciences, Shirley, NY, 11967 as item 438517.

Mono-4'-hydroxyethylquercetin-7-glucuronide and mono-3'hydroxyethylquercetin-7-glucuronide can be obtained from TLC Pharmaceutical Standards (Aurora, Ontario, Canada) as compounds in the inventory "under development". can.

As used herein, "glycoside" refers to a compound containing a sugar moiety attached to the compound via a glycosidic bond. Thus, if a glycoside follows the compound name (eg, hydroxyethyl kelcetin), the "glycoside" modifies the particular compound indicated by that name, and as a result, the modified compound is a compound via a glycosidic bond. Will contain sugar moieties bound to. The sugar portion of the glycoside may be a monosaccharide or a polysaccharide. Examples of glycosides include, but are not limited to, glucuronide, glucoside and rutinose. In some embodiments, the glycoside is glucuronide. In some embodiments, the glycoside is a glucoside.

In some embodiments, the hydroxyethyl quercetin glycoside is a hydroxyethyl quercetin-3-O-glycoside (eg, hydroxyethyl quercetin-3-O-glucuronide, eg, mono-3'-O-hydroxyethyl quercetin-3-O). -Glucuronide or mono-4'-O-hydroxyethylquercetin-3-O-glucuronide).

In some embodiments, the hydroxyethyl quercetin glycoside is a hydroxyethyl quercetin-5-O-glycoside (eg, hydroxyethyl quercetin-5-O-glucuronide, eg, mono-3'-O-hydroxyethyl quercetin-5-O. -Glucuronide or mono-4'-O-hydroxyethylquercetin-5-O-glucuronide).

In some embodiments, the hydroxyethyl quercetin glycoside is a hydroxyethyl quercetin-7-O-glycoside (eg, hydroxyethyl quercetin-7-O-glucuronide, eg, mono-3'-O-hydroxyethyl quercetin-7-O. -Glucuronide or mono-4'-O-hydroxyethylquercetin-7-O-glucuronide).

In some embodiments, the hydroxyethyl quercetin glycoside is a hydroxyethyl quercetin-3'-O-glycoside (eg, hydroxyethyl quercetin-3'-O-glucuronide, eg, mono-7-O-hydroxyethyl quercetin-3'. -O-glucuronide).

In some embodiments, the hydroxyethyl quercetin glycoside is a hydroxyethyl quercetin-4'-O-glycoside (eg, hydroxyethyl quercetin-4'-O-glucuronide, eg, mono-7-O-hydroxyethyl quercetin-4'. -O-glucuronide).

In some embodiments, the glycoside component of the mono-3'-O-hydroxyethylquercetin-glycoside is glucuronide. In some embodiments, the glucuronide component is 7-O-glucuronide, thereby producing mono-3'-O-hydroxyethylquercetin-7-O-glucuronide, see Structural Formula I). .. In another aspect, the glycoside component of mono-3'-O-hydroxyethylquercetin-glycoside is a glucoside. Mono-3'-hydroxyethylquercetin-7-O-glucuronide is available from Sinco Pharmachem Inc. , West Bloomfield Township, MI.

One embodiment is a compound comprising hydroxyethylquercetin-7-O-glucuronide or a pharmaceutically acceptable salt thereof.

Another aspect is structural formula I:

によって表わされる化合物又はその医薬的に許容される塩である。

A compound represented by or a pharmaceutically acceptable salt thereof.

The second aspect is Structural Formula II :.

によって表わされる化合物又はその医薬的に許容される塩である。

A compound represented by or a pharmaceutically acceptable salt thereof.

The third aspect is structural formula III :.

によって表わされる化合物又はその医薬的に許容される塩である。

A compound represented by or a pharmaceutically acceptable salt thereof.

The fourth aspect is structural formula IV :.

によって表わされる化合物又はその医薬的に許容される塩である。

A compound represented by or a pharmaceutically acceptable salt thereof.

Troxerutin has structural formula V:

によって表される化合物である。

It is a compound represented by.

Composition One or more compounds disclosed herein (eg, a metabolite of hydroxyethylrutoside, hydroxyethylquercetin-7-O-glucuronide, any compound of structural formulas I-IV) or pharmaceuticals thereof. A composition (eg, a pharmaceutically acceptable composition) comprising an acceptable salt and a pharmaceutically acceptable carrier or excipient is provided herein. In certain embodiments, the compositions of the invention are formulated for administration to a subject (eg, a patient) in need of the composition. In some embodiments, the compositions of the invention are formulated for oral, intravenous, subcutaneous, intraperitoneal or dermatological administration to a subject in need of the composition.

In some embodiments, the composition of the invention further comprises a second acid. In one embodiment, the second acid is selected from citric acid, hydrochloric acid and combinations thereof. As will be appreciated by those skilled in the art, the glucuronide compounds described herein are acids in the described compositions (ie, the first acid), so a second acid is added to the composition. can do. Although not bound by any particular theory, the second acid is believed to increase the gastric retention time of the compound in its protonated (neutral) form when administered. ..

The phrase "pharmaceutically acceptable carrier or excipient" was administered at a dose sufficient to deliver a therapeutic dose of the drug without disrupting the pharmacological activity of the drug formulated with it. Refers to a non-toxic carrier or excipient that is sometimes non-toxic. Pharmaceutically acceptable carriers or excipients that can be used in the compositions described herein include ion exchangers, alumina, aluminum stearate, lecithin, self-emulsifying drug delivery systems (SEDDS), eg. , D-α tocopherol polyethylene glycol 1000 succinate, surfactants used in pharmaceutical forms such as Tween or other similar polymer delivery matrices, serum proteins such as human serum albumin, buffers such as phosphates. Glycin, sorbic acid, potassium sorbate, partial glyceride mixture of saturated vegetable fatty acids, water, salts or electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, tri. Examples include, but are not limited to, magnesium silicate, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and wool fat. Cyclodextrins, such as α-, β- and γ-cyclodextrins, or chemically modified derivatives such as hydroxyalkylcyclodextrins and other solubilized derivatives, including 2- and 3-hydroxypropyl-β-cyclodextrins. It can also be used advantageously to enhance the delivery of the agents described herein.

The compositions described herein are described locally, intrarectally, intranasally, eg, orally, parenterally, by inhalation (eg, intrabronchial, intranasal or oral inhalation, intranasal droplets). It can be administered by a method of administration that is parenteral or non-oral, such as buccal, intravaginally, edible, transdermally, or via an implantable reservoir. In some embodiments, the provided compound or composition can be administered intravenously and / or intraperitoneally. Administration may be local or systemic, as shown. The preferred mode of administration may vary depending on the particular compound selected.

The terms "parenteral" or "parenterally" used interchangeably herein include injection, subcutaneous, intradermal, intravenous, intramuscular, intradermal, intraocular, and the like. Includes intravitreal, intra-arterial, intra-arterial, intra-synamic, intrathoracic, intrathecal, intralesional, intrahepatic, intraperitoneal and intracranial injection or infusion techniques.

The compositions provided herein include, but are not limited to, capsules, tablets, pills, aqueous suspensions, dispersions and solutions that can be orally administered in any orally acceptable dosage form. can. For tablets for oral use, commonly used carriers include lactose and corn starch. Lubricants such as magnesium stearate are also typically added. For oral administration in capsule form, useful diluents include lactose and dried corn starch. If an aqueous suspension and / or emulsion is required for oral use, the active ingredient may be suspended or dissolved in the oil phase and combined with an emulsifier and / or suspending agent. If desired, certain sweeteners, flavors or colorants may also be added.

In some embodiments, the oral formulation is formulated for immediate release or sustained / delayed release.

Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In such solid dosage forms, the active compound is at least one inert pharmaceutically acceptable excipient or carrier, such as sodium citrate or dicalcium phosphate and / or (a) filler or augmentation. Agents such as starch, lactose, sucrose, glucose, mannitol and silicic acid, (b) binders such as carboxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and acacia, (c) moisturizers such as glycerol, (D) Disintegrants such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates and sodium carbonates, (e) dissolution retarders such as paraffin, (f) absorption enhancers, eg. Tertiary ammonium salts, (g) wetting agents such as acetyl alcohol and glycerol monostearate, (h) absorbents such as kaolin and bentonite clay, and (i) lubricants such as talc and calcium stearate. It is mixed with magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate and mixtures thereof. For capsules, tablets and pills, the dosage form may also include a buffer.

Suitable compositions for buccal or sublingual administration include tablets, lozenges and lozenges, where the active ingredient is formulated with carriers such as sugar and acacia, tragacanth or gelatin and glycerin. ..

Similar types of solid compositions can also be used as fillers in soft and hard filled gelatin capsules using excipients such as lactose or lactose, as well as high molecular weight polyethylene glycols and the like. Solid dosage forms of tablets, sugar-coated tablets, capsules, pills and granules can be prepared using coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical pharmaceutical technology. They may optionally contain an opacity agent and, in an optional delayed manner, release only the active ingredient (s) in a particular portion of the gastrointestinal tract or It may be a composition that preferentially releases it. Examples of embedded compositions that can be used include polymeric substances and waxes.

The compounds described herein may be in microencapsulated form with one or more excipients. In such a solid dosage form, the compound can be mixed with at least one inert diluent, such as sucrose, lactose or starch. Such dosage forms, as is customary, may also include additional substances other than the Inactive Diluent, such as tablet lubricants and other tableting aids, such as magnesium stearate and microcrystalline cellulose.

The composition for oral administration may be designed to protect the active ingredient from degradation as it passes through the gastrointestinal tract, for example, by coating the outer coating of the formulation on tablets or capsules.

In another embodiment, the compounds described herein may be provided in a long-term (or "delayed" or "sustained") release composition. This delayed release composition comprises a compound in combination with a delayed release component. Such compositions allow targeted release of the provided agent into the lower gastrointestinal tract, eg, the small intestine, large intestine, colon and / or rectum. In certain embodiments, the delayed release composition further comprises an enteric or pH dependent coating, such as cellulose acetate phthalate and other phthalates (eg, polyvinyl acetate phthalate, methacrylates). Alternatively, the delayed release composition provides controlled release into the small intestine and / or colon by providing a pH sensitive methacrylate coating, a pH sensitive polymer microsphere or a polymer that is degraded by hydrolysis. The delayed release composition can be formulated with a hydrophobic or gelling excipient or coating. Colon delivery is by coatings digested by bacterial enzymes such as amylose or pectin, by pH-dependent polymers, by Pulsincap of hydrogel plugs, by time-dependent hydrogel coatings, and / or to aromatic-bound coatings. Further can be provided by the linked acrylic acid.

The compositions described herein can also be administered in the form of suppositories for rectal administration. They mix the compounds described herein with suitable non-irritating excipients that are solid at room temperature but liquid at rectal temperature and thus dissolve in the rectum to release the drug. It can be prepared by. Such materials include cocoa butter, beeswax and polyethylene glycol.

For ophthalmic use, the composition is chloride as a micronized suspension in isotonic pH-adjusted sterile physiological saline, or, for example, as a solution in isotonic pH-adjusted sterile physiological saline. It can be formulated with or without a preservative such as benzylalconium. Alternatively, for ophthalmic use, the composition can be formulated in an ointment such as petrolatum.

The composition can also be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well known in the art of pharmaceutical formulations, such as benzyl alcohol or other suitable preservatives, absorption enhancers to enhance bioavailability, fluorocarbons and / or other conventional methods. It can be prepared as a solution in physiological saline using a solubilizer or a dispersant.

The amount of compound described herein that can be combined with the carrier material to produce a composition in a single dosage form depends on the subject being treated, the particular mode of administration and the activity of the agent used. Will fluctuate. The composition can be formulated so that a dosage of about 0.01 mg / kg to about 100 mg / kg body weight / day can be administered to a subject receiving the composition.

Specific dosage and treatment regimens for any particular patient include specific drug activity, age, weight, general health, gender, diet, dosing time, rate of excretion, drug combination, treatment. It should be understood that it will depend on a variety of factors, including the severity of the particular disease / disorder being treated by the physician. The amount of compound in the composition also depends on the particular compound in the composition.

The composition can be in the form of a sterile injection preparation, eg, an aqueous or oily suspension for sterile injection. The suspension can be formulated according to techniques known in the art using suitable dispersants or wetting agents (eg, Tween 80, etc.) and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, such as a 1,3-butanediol solution. Acceptable vehicles and solvents that can be used include mannitol, water, Ringer solution and isotonic sodium chloride solution. In addition, sterile non-volatile oils are conventionally used as solvents or suspension media. For this purpose, any sterile non-volatile oil containing synthetic monoglycerides or diglycerides can be used. Fatty acids such as oleic acid and its glyceride derivatives are useful in the preparation of injections as well as naturally pharmaceutically acceptable oils such as olive oil or castor oil, especially in their polyoxyethylated versions. .. These oils or suspensions are also long chain alcohol diluents or dispersants or carboxymethyl cellulose, or similar commonly used formulations of pharmaceutically acceptable dosage forms such as emulsions and / or suspensions. It may also contain a dispersant. Other commonly used surfactants commonly used in the manufacture of pharmaceutically acceptable solids, liquids or other dosage forms, such as Tween or Span and / or other similar emulsifiers or Bioavailability enhancers can also be used for formulation purposes.

In some embodiments, the compounds described herein (eg, a metabolite of hydroxyethylrutoside, hydroxyethylquercetin-7-O-glucuronide, compounds of structural formulas I-IV) or pharmaceuticals thereof. Compositions containing a qualifyingly acceptable salt may also include one or more other therapeutic agents. When the composition of the invention comprises a combination of a compound described herein and one or more other therapeutic agents, the agent is about 1 to 1 of the dosage normally administered in a monotherapy regimen. It should be present at a dosage level of 100%, more preferably about 5% to about 95%. Additional agents (s) are part of a single dosage form mixed with the compounds described herein or pharmaceutically acceptable salts thereof in a single composition. obtain. Alternatively, the additional agent (s) can be administered separately from the compounds described herein or pharmaceutically acceptable salts thereof as part of a multiple dose regimen.

Thus, the compounds described herein (eg, a metabolite of hydroxyethylrutoside, hydroxyethylquercetin-7-O-glucuronide, any compound of structural formulas I-IV) or pharmaceutically acceptable thereof. Kits are also provided that include salts and additional agents (eg, a second acid). In one embodiment, the kit comprises an amount of a compound described herein or a pharmaceutically acceptable salt thereof, in an amount effective to treat the disease, disorder or condition described herein. Includes an amount of additional drug (s) that is effective in treating the disease, disorder or condition described herein.

The compositions described herein are, for example, injection, intravenous, intraarterial, intravitreal, intravitreal, subcutaneous, oral, buccal, intranasal, transmucosal, topical, ophthalmic preparation, or inhalation. By any of the methods described herein, with dosages ranging from about 0.5 mg / kg to about 100 mg / kg body weight, or as an alternative, from about 1 mg / dose to about 5000 mg / dose. Alternatively, dosages ranging from about 1 mg / dose to about 1,000 mg / dose can be administered every 4 to 120 hours (eg, about every 24 hours) or according to the requirements of the particular drug. In one embodiment, the dosage is about 450 mg / dose. Typically, the composition will be administered about 1 to about 6 times per day (eg, 1, 2, 3, 4, 5 or 6 times), or as an alternative, as a continuous infusion. The amount of active ingredient that can be combined with the carrier material to produce a single dosage form will vary depending on the subject being treated and the particular mode of administration. A typical preparation will contain from about 5% to about 95% active compound (weight / weight). Alternatively, the preparation may contain from about 20% to about 80% active compound (weight / weight).

Lower or higher doses may be required. The specific dosage and treatment regimen for any particular patient is the activity, age, weight, general health, gender, diet, dosing time, excretion rate, drug combination, disease of the specific drug used. It will depend on the severity and course of the condition or condition, the patient's tendency towards the disease, condition or condition, and the judgment of the treating physician.

When the condition of the subject improves, a maintenance dose of the compound of the invention (eg, a metabolite of hydroxyethylrutoside, hydroxyethylquercetin-7-O-glucuronide, any compound of structural formulas I-IV) or pharmaceutical thereof. Permissible salts, compositions or combinations may be administered as needed. Subsequently, the dosage and / or frequency of administration may be reduced to a level at which the improved condition is maintained if the symptoms are alleviated to the desired level as a function of the symptoms. However, subjects may require long-term intermittent treatment upon recurrence of disability symptoms.

Method Kiensler, Eur. J. Clin. Pharmacol. , 2002, 58, 395-402 are two major metabolites of plasma levels detectable by oral administration of hydroxyethylrutoside-containing VENORUTON® in human volunteers, mono-3'-O-hydroxyethyl. It was reported that quercetin-glucuronide (mono-3'-O-HEQG) and mono-4'-hydroxyethylquercetin-glucuronide were produced.

Mono-3'-O-HEQG treats prenatal or postpartum depression as i) as a hydroxyethylquercetin-containing compound, as it is likely to have the same beneficial effects on cortisol as troxerutin and monoHER. As well as ii) it has an exceptionally long terminal half-life of at least 17 hours (Kienzler, Eur. J. Clin. Pharmacol., 2002, 58, 395-402 FIG. 2). This makes it attractive as a monotherapy because it can be administered only once a day. It is believed that once-daily administration means improved ease of use as compared to the current multiple daily administrations of hydroxyethylrutoside.

However, there are some pharmacological problems with Mono-3'-O-HEQG. Kiensler has reported the detection of mono-3'-O-HEQG as a VENORUTON® metabolite, but when VENORUTON® is provided in low doses (0.5 g), mono-3'. -O-HEQG was only detectable in 13 of the 16 volunteers. Similarly, Hasler-Nguyen, Philology, 2004, 19, 131-6 attempted oral administration of deglycosylated VENORUTON® (ie, hydroxyethylquercetin) to rats, mono-3'-O-HEQG. Reported that was not detectable. Therefore, it is believed that oral administration of conventional mixtures of HEQ-containing compositions cannot reliably produce the described mono-3'-O-HEQG molecules as metabolites in plasma.

Furthermore, a method of reliably producing mono-3'-O-HEQG in the bloodstream is independent of the liver and produces it from a molecule-free starting material that is hydroxyethylated at the 3'position alone. It is thought to avoid doing so. Rather, the method for reliably producing this molecule is to administer a rutin-based molecule that is hydroxyethylated at the 3'position alone.

A method for achieving detectable levels of mono-3'-hydroxyethylquercetin glucuronide in a subject, the subject being mono-3'-O-hydroxyethylquercetin-glycoside or a pharmaceutically acceptable salt thereof. And a method comprising administering a pharmaceutically acceptable carrier or diluent is provided herein. Oral administration of a composition comprising mono-3'-O-hydroxyethylquercetin and a pharmaceutically acceptable carrier, a method of ensuring that detectable levels of mono-3'-O-HEQG are achieved. Methods including are also provided.

Although not bound by theory, mono-3'-O-hydroxyethylquercetin-glycosides (estimated log P = 0-1) are mono-3'-O-hydroxyethylquercetin (log P). It is expected that it will be more water-soluble than (estimated to be 2-3) and can still cross the cell wall, and as a result, it is more likely to be bio-available.

Mono-3'-O-hydroxyethylquercetin-glycosid can be cleaved in the colon by the colonic microbial flora to produce mono-3'-O-hydroxyethylquercetin (mono-3'-O-HEQ). Is expected. From there, mono-3'-O-HEQ is expected to migrate through the colon wall to the liver, where it is glucuronidated and again mono-3'-O-hydroxyethylquercetin lechronide. .. Jaganath. , Free Rad. Biol. Med. , 47, 2009, 1180-9 report that rutin is cleaved by the bacterial microbial flora in the colon, and Barrow, Xenobiotica, May 1974, 734-54 report that hydroxyethylrutoside is cleaved by the microbial flora in the colon. I am reporting that I will be disconnected. However, there is at least some evidence that glucuronide can be absorbed in the small intestine. Stein-Texier, Drag Metab Dispos. , 1998 May, 26, 5, 383-7. One recent document (Yang, Scientific Reports, 6: 35460, 2016) examines a similar molecule, quercetin-3-glucuronide, which is a lumen ratase, phlorizin, prior to its absorption into the blood. It has been shown to be treated either by hydrolase deconjugation or by the intestinal microbial flora. Therefore, although it is relatively clear that mono-3'-O-hydroxyethylquercetin-glycoside is cleaved in the gastrointestinal tract, it is somewhat uncertain where the cleavage occurs. It is possible that glycosides containing two sugars are cleaved in the colon, while glycosides containing one sugar are cleaved in the small intestine.

Hydroxyethylrutoside may be useful in preventing postpartum depression by increasing norepinephrine levels in the brain. Hydroxyethylrutoside prevents the metabolism of norepinephrine, thereby prolonging the lifespan of norepinephrine (and increasing venous tone). Araujo, Arch. Int. , Pharmacoldyn. , Ther. , 1985 Oct. , 277, 2, 192-202 (VENORUTON® blocks norepinephrine inactivation). Norepinephrine is associated with arousal. Strahler, Biol Psychol. 2013 Sep; 94 (1): 160-6. doi: 10.016 / j. biopsycho. 2013.06.002. Epub 2013 Jun 13 investigated the norepinephrine and epinephrine responses to physiological and pharmacological stimuli in chronic fatigue syndrome (CFS) and found that inappropriate catecholaminergic responses to physical exercise could contribute to CFS symptoms. I concluded. Blier, Neuropsychiatry Dis Treat. 2011; 7 (Suppl 1): 15-20, the attenuation of the activity of norepinephrine and dopamine neurons mediated by inhibitory 5-HT2A and 5-HT2C receptors, respectively, causes fatigue and energy in depressed patients who received SSRIs. He reported that he could explain the residual symptoms of deficiency and loss of pleasure. Some studies conclude that postpartum fatigue predicts postpartum depression. In a study of 37 postpartum women, 13 of 14 who evaluated themselves as significantly tired at 2 weeks postpartum developed PPD symptoms at 1 month postpartum. I arrived. Bozosky, J. Mol. Obstet. Gynec. , Neonal Nursing, 31, 2002, 436-443. On days 7, 14 and 28, a significant correlation was found between postpartum fatigue and symptoms of PPD, and the level of fatigue on day 14. Predicted future onset of PPD in 10 of 11 females. Corwin, J. et al. Obstet. Gynec. , Neotal Nursing, 2005, Sept-Oct. , 34, 5, 557-86. Fatigue and depressive symptoms were moderate to severely correlated at 1 month, 3 months, and 6 months after delivery. Doering-Runquist, "Severe Focus and Depressive Symptoms in lower-Income Urban Postpartum Woman", Western J Nurs Res. , 2009.

A method of inhibiting the metabolism of norepinephrine in a subject requiring inhibition of the metabolism of norepinephrine, wherein the subject is in an effective amount of a compound described herein (eg, a metabolite of hydroxyethylrutoside, hydroxy). Ethylkelcetin-7-O-glucuronide, a compound of any of structural formulas I-IV) or a pharmaceutically acceptable salt thereof, or an effective amount of a compound described herein or a pharmaceutically acceptable compound thereof. Provided herein are methods comprising administering a composition comprising a salt.

It is also a method of treating depression in a subject in need of treating the depression in an effective amount of a compound described herein (eg, a metabolite of hydroxyethylrutoside, hydroxyethylquercetin). -7-O-glucuronide, a compound of any of structural formulas I-IV) or a pharmaceutically acceptable salt thereof, or an effective amount of a compound described herein or a pharmaceutically acceptable salt thereof. Methods comprising administering the composition are also provided herein.

Administration of hydroxyethylrutoside is safe for pregnant women and is considered to correct cortisol-related problems, so it is necessary to treat perinatal, prenatal (ie, prenatal) and / or postpartum depression. A method of treating perinatal, prenatal (ie, prenatal) and / or postpartum depression in a subject, wherein an effective amount of a compound described herein (eg, hydroxyethyl). A metabolite of rutoside, hydroxyethylkelcetin-7-O-glucuronide, a compound of any of structural formulas I-IV) or a pharmaceutically acceptable salt thereof, or an effective amount of a compound described herein or Also provided herein are methods comprising administering a composition comprising the pharmaceutically acceptable salt.

The term "treat" or "treatment" is therapeutically intended to delay (reduce) unwanted physiological changes or disease, or to produce beneficial or desired clinical outcomes during treatment. Refers to treatment. Beneficial or desired clinical outcomes, whether detectable or undetectable, are alleviation of symptoms, reduction of the degree of disease / disorder, stabilization of disease / disorder (ie, exacerbation). Not), delaying or slowing the progression of the disease / disorder, ameliorating or alleviating the disease / disorder state, and / or remission (partially or wholly). Those in need of treatment include subjects who already have undesired physiological changes or diseases / disorders, as well as subjects who are prone to have physiological changes or diseases / disorders.

In one embodiment, the subject (eg, patient) is a mammal (eg, human, non-human primate, cow, sheep, goat, horse, dog, cat, rabbit, guinea pig, rat, mouse, or other cow). , Sheep, horses, dogs, cats or rodents). In one embodiment, the subject is a human. In one embodiment, the subject is a pregnant human. In some embodiments, the pregnant human is in the second or third trimester of pregnancy. In some embodiments, the pregnant human is in late pregnancy. In some embodiments, the pregnant human is in metaphase. In some embodiments, the subject's pregnancy is about 20-28 weeks gestation. In some embodiments, the subject is a human who gave birth about 1 to about 4 weeks ago. In one embodiment, the subject is a postnatal human. In some embodiments, the human is postpartum. In some embodiments, the human gave birth within about 4 weeks, or the human gave birth within about 1 week.

"Subjects in need of" refers to subjects who have or are at risk of developing the diseases or conditions described herein (eg, depression and / or metabolic imbalance of norepinephrine). .. If you are a skilled healthcare professional (eg, a physician or clinician), the subject has or has the disease or condition described herein (eg, depression and / or metabolic imbalance of norepinephrine). It is possible to determine whether or not there is a risk of developing the disease.

As used interchangeably herein, "therapeutically effective amount" or "effective amount" refers to an amount effective to obtain the desired therapeutic result at the required dosage and duration. The therapeutically effective amount may vary depending on factors such as the individual's disease state, age, sex and body weight, and the ability of the therapeutic agent or combination of therapeutic agents to elicit the desired response in the individual. Exemplary indicators of one effective therapeutic agent or combination of therapeutic agents include, for example, improving the health of the patient or reducing the symptoms of depression.

The effective amount of the compound to be administered can be determined by one of ordinary skill in the art using the guidelines provided herein and other methods known in the art, eg, the particular compound selected and / Or depends on multiple factors, including composition, subject's age, susceptibility, tolerance to drugs and general health. For example, suitable dosages are about 0.001 mg / kg to about 100 mg / kg, about 0.01 mg / kg to about 100 mg / kg, about 0.01 mg / kg to about 10 mg / kg, about 0 per treatment. It can be from 0.01 mg / kg to about 1 mg / kg body weight. Determining dosages for a particular drug, subject and disease is well within the ability of one of ordinary skill in the art. Preferably, the dosage does not cause or bring about minimal side effects (eg, immunogenic response, nausea, dizziness, gastric discomfort, hyperviscosity syndrome, congestive heart failure, stroke, pulmonary edema).

The compounds described herein (eg, a metabolite of hydroxyethylrutoside, hydroxyethylquercetin-7-O-glucuronide, any compound of structural formulas I-IV) or pharmaceutically acceptable salts thereof. , For example, they can be administered as single or multiple doses in an order and schedule suitable to achieve the desired therapeutic effect (eg, inhibition of norepinephrine metabolism). Suitable dosages and dosing regimens can be determined by a skilled clinician.

In some embodiments, administration of the compounds / compositions of the invention may comprise administration of an acidifying agent, such as betaine, or a pharmaceutically acceptable salt thereof, or an acidic liquid medium. In one embodiment, the acidic liquid medium has a pH of less than about 3. In one embodiment, the acidic liquid medium comprises citric acid, acetic acid or hydrochloric acid, or a combination of citric acid, acetic acid or hydrochloric acid. In one embodiment, the acidic liquid medium comprises vinegar or citrus juice, or a combination of vinegar or citrus juice. Examples of other acids useful herein include hydrobromic acid, phosphoric acid, sulfuric acid, perchloric acid, oxalic acid, maleic acid, tartaric acid, succinic acid and malonic acid.

Acidifying agents or acidic liquid media are provided to increase the gastric retention time of the protonated form of the compound. The fasting stomach has a low pH and provides the desired protonated (neutral) glucuronide morphology, but drains water within 15 minutes (Okabe, Brit. J. Anasthesia, 114, 1, 77-82, 2015), thereby allowing exposure of the compound (ie, glucuronide) in the stomach for only 15 minutes. Conversely, the post-feeding stomach has a long gastric emptying time (3 hours), but its higher pH results in an undesired anionic glucuronide form that is poorly absorbed. Therefore, it is desirable to deliver the desired neutral glucuronide with a long gastric residence time. Therefore, an acidifying agent and / or an acidic liquid medium is provided with the composition to increase the gastric retention time of the protonated (neutral) form of glucuronide and increase its solubility.

The compounds described herein (eg, a metabolite of hydroxyethylrutoside, hydroxyethylquercetin-7-O-glucuronide, any compound of structural formulas I-IV) or pharmaceutically acceptable salts thereof. It can also be administered in combination with one or more other treatments or treatments, such as additional therapeutic agents. With respect to the administration of a compound in combination with one or more other therapeutic agents or treatments (adjuvant, targeted, etc.), the agent is typically administered as a single dose (eg, injection, infusion, oral). Subsequently, if desired or instructed, repeated doses are given at specific intervals (eg, 1 hour or longer).

When administered in combination therapy, the compound or pharmaceutically acceptable salt thereof may be before, after, or other therapeutic agents (eg, additional (eg, additional) agents). Can be administered at the same time (multiple types of drugs). When administered simultaneously (eg, in parallel), the compound or a pharmaceutically acceptable salt thereof and other therapeutic agents may be separate or identical formulations. Alternatively, the compound or a pharmaceutically acceptable salt thereof and other therapeutic agents are sufficient to allow for an appropriate time frame determined by a skilled clinician (eg, duplication of pharmaceutical effects of the therapeutic agent). Within time), it can be administered sequentially as a separate composition.

The actual dose of therapeutic agent and treatment regimen can be determined by the physician or clinician, taking into account the nature of the disease, other treatments being received, and the characteristics of the subject.

(Example 1)
This non-limiting hypothetical example describes embodiments of the compositions of the invention.

The pharmaceutical composition of flavone glucuronide comprises:

Optionally, the composition may contain 50 mg of other flavonoids, such as hesperidin.

Similarly, the pharmaceutical composition of flavone glucuronate comprises:

Optionally, the composition may contain 50 mg of other flavonoids, such as hesperidin.

Similarly, the pharmaceutical composition of hydroxyethyl quercetin-7-O-glucuronide comprises:

Optionally, the composition may contain 50 mg of other flavonoids, such as hesperidin.

The relevant teachings of all patents, published patents and references cited herein are hereby incorporated by reference in their entirety.

Although exemplary embodiments are specifically shown and described, those skilled in the art will appreciate a variety of embodiments and details without departing from the scope of the embodiments included in the appended claims. You will understand that you can make any changes to this.

Claims (20)

A pharmaceutical composition comprising hydroxyethylquercetin-O-glucuronide or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or diluent. The pharmaceutical composition according to claim 1, wherein the composition is formulated for oral administration. The pharmaceutical composition according to claim 1, further comprising a second acid. The pharmaceutical composition according to claim 3, wherein the second acid is citric acid, hydrochloric acid, or a combination thereof. The pharmaceutical composition according to claim 1, wherein the hydroxyethyl quercetin-O-glucuronide is hydroxyethyl quercetin-3-O-glucuronide. The pharmaceutical composition according to claim 1, wherein the hydroxyethyl quercetin-O-glucuronide is hydroxyethyl quercetin-5-O-glucuronide. The pharmaceutical composition according to claim 1, wherein the hydroxyethyl quercetin-O-glucuronide is hydroxyethyl quercetin-7-O-glucuronide. The pharmaceutical composition according to claim 1, wherein the hydroxyethyl quercetin-O-glucuronide is hydroxyethyl quercetin-3'-O-glucuronide. The pharmaceutical composition according to claim 1, wherein the hydroxyethyl quercetin-O-glucuronide is hydroxyethyl quercetin-4'-O-glucuronide. The pharmaceutical composition according to claim 1, wherein the hydroxyethyl quercetin-O-glucuronide is monohydroxyethyl quercetin-O-glucuronide. The pharmaceutical composition according to claim 10, wherein the monohydroxyethylquercetin-O-glucuronide is mono-3'-O-hydroxyethylquercetin-O-glucuronide. The pharmaceutical composition according to claim 10, wherein the monohydroxyethylquercetin-O-glucuronide is mono-4'-O-hydroxyethylquercetin-O-glucuronide. A method of inhibiting the metabolism of norepinephrine in a subject who needs to inhibit the metabolism of norepinephrine.
A method comprising administering to the subject an effective amount of the pharmaceutical composition according to claim 1. 13. The method of claim 13, wherein the administration is oral administration. 13. The method of claim 13, further comprising administering an acidifying agent. 15. The method of claim 15, wherein the acidifying agent is betaine or a pharmaceutically acceptable salt thereof. 15. The method of claim 15, wherein the acidifying agent is an acidic liquid medium. 17. The method of claim 17, wherein the acidic liquid medium has a pH of less than about 3. 18. The method of claim 18, wherein the acidic liquid medium comprises citric acid, acetic acid or hydrochloric acid, or a combination of the citric acid, the acetic acid or the hydrochloric acid. 17. The method of claim 17, wherein the acidic liquid medium comprises vinegar or citrus juice, or a combination of said vinegar or said citrus juice.